The aim of this research proposal is to study the stereospecific glucose transport system in single functional presynaptic nerve endings, its modification by insulin and its relevance to diabetic neuropathy. Recently, an electrophysiological method was developed in our laboratory to study glucose transport at a single cell level, which employs the known physiological phenomenon of hyperosmotic neurosecretion: substances that penetrate through the presynaptic membrane cause a transient hyperosmotic neurosecretion, while non-penetrating substances induce a sustained hyperosmotic neurosecretion. In preliminary studies we were able to show that the motor terminal of the amphibian neuromuscular junction possesses a stereospecific D-glucose transport system which is sensitive to insulin. Using electrophysiological techniques and ON-LINE computer-assisted data collection and analysis, we would like to extend these studies to the mammalian nervous system and to examine in detail the following: 1. To characterize the presynaptic glucose transport system regarding its kinetic behavior, selectivity and specificity. 2. To examine the role of glucose transport in the regulation of transmitter release. 3. To characterize the action of insulin on glucose transport in the presynaptic motor nerve ending and on the properties of synaptic transmission. 4. To examine the changes in the glucose transport system in experimental insulin-dependent diabetes mellitus and its relevance in the development of experimental diabetic neuropathy. We believe that this approach may provide useful information regarding the cellular handling of glucose, which is one of the key metabolic substrates of neuronal function, and may contribute to the understanding of the changes in peripheral nervous system during early stages of the pathogenesis of experimental diabetes mellitus.